Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease
Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease
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DOI：
10.1016/j.neurobiolaging.2010.05.021
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Ciriolo, Maria R.
中科院分区：
文献类型：
--
作者：
Filomeni, Giuseppe;Graziani, Ilaria;Ciriolo, Maria R.
本研究旨在阐明山奈酚在鱼藤酮急性毒性模型中的神经保护作用机制。我们证明，山奈酚，而不是槲皮素，杨梅素或白藜芦醇，保护SH-SY 5 Y细胞和原代神经元从鱼藤酮毒性，减少半胱天冬酶裂解和凋亡细胞核观察。活性氧（ROS）水平和线粒体羰基显着降低。线粒体网络、跨膜电位和氧消耗也被深度保存。我们证明，主要事件负责山萘酚介导的抗凋亡和抗氧化作用是增强线粒体营业额的自噬。事实上，荧光和电子显微镜分析显示线粒体分裂率和含线粒体的自噬体增加。此外，自噬体结合的微管相关蛋白轻链-3（LC 3-II）在山奈酚治疗过程中增加，自噬的化学/遗传抑制剂消除了山奈酚的保护作用。自噬还对用于再现帕金森病（PD）的典型特征的其他线粒体毒素（1-甲基-4-苯基吡啶，百草枯）提供保护，但对不直接影响线粒体的凋亡刺激（H2 O2，6-羟基多巴胺，星形孢菌素）无效。大鼠脑切片的纹状体神经元能反应也被山奈酚保留，表明山奈酚在帕金森病中具有更广泛的保护作用。总的来说，这些数据为山萘酚被鉴定为具有潜在治疗能力的自噬增强剂提供了进一步的证据。(C)2012 Elsevier Inc. All rights reserved.
This study aims to elucidate the processes underlying neuroprotection of kaempferol in models of rotenone-induced acute toxicity. We demonstrate that kaempferol, but not quercetin, myricetin or resveratrol, protects SH-SY5Y cells and primary neurons from rotenone toxicity, as a reduction of caspases cleavage and apoptotic nuclei are observed. Reactive oxygen species (ROS) levels and mitochondrial carbonyls decrease significantly. Mitochondrial network, transmembrane potential and oxygen consumption are also deeply preserved. We demonstrate that the main event responsible for the kaempferol-mediated antiapoptotic and antioxidant effects is the enhancement of mitochondrial turnover by autophagy. Indeed, fluorescence and electron microscopy analyses show an increase of the mitochondrial fission rate and mitochondria-containing autophagosomes. Moreover, the autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) increases during kaempferol treatment and chemical/genetic inhibitors of autophagy abolish kaempferol protective effects. Autophagy affords protection also toward other mitochondrial toxins (1-methyl-4-phenyilpiridinium, paraquat) used to reproduce the typical features of Parkinson's disease (PD), but is inefficient against apoptotic stimuli not directly affecting mitochondria (H2O2, 6-hydroxydopamine, staurosporine). Striatal glutamatergic response of rat brain slices is also preserved by kaempferol, suggesting a more general protection of kaempferol in Parkinson's disease. Overall, the data provide further evidence for kaempferol to be identified as an autophagic enhancer with potential therapeutic capacity. (C) 2012 Elsevier Inc. All rights reserved.